2-Decarboxy-2-aminomethyl-4-halo-5,9-epoxy-9-deoxy-PGF1 compounds

ABSTRACT

The present invention relates to novel 2-decarboxy-2-aminomethyl-4-halo-5,9-epoxy-9-deoxy-PGF 1  compounds, which are intermediates useful for the preparation of corresponding 5,9α-epoxy-9-deoxy-PGF 1  and 5,9-epoxy-9-deoxy-4,5-didehydro-PGF 1  compounds. These end products are employed for induction of a variety of prostacyclinlike pharmacological effects. Accordingly, these end products are useful pharmacological agents for the same purposes for which prostacyclin is employed.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a divisional application of U.S. Ser. No.932,981, filed Aug. 11, 1978, now pending issuance as a United Statespatent; which is a divisional application of U.S. Ser. No. 819,856,filed July 28, 1977, now U.S. Pat. No. 4,123,441; which is acontinuation-in-part application of U.S. Ser. No. 725,546, filed Sept22, 1976, now abandoned; which is a continuation-in-part application ofUnited States Ser. No. 716,960, filed Aug. 23, 1976, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel2-decarboxy-2-aminomethyl-4-halo-5,9-epoxy-9-deoxy-PGF₁ compounds, whichare intermediates useful for the preparation of corresponding5,9α-epoxy-9-deoxy-PGF₁ and 5,9-epoxy-9-deoxy-4,5-didehydro-PGF₁compounds. These end products are employed for induction of a variety ofprostacyclin-like pharmacological effects. Accordingly, these endproducts are useful pharmacological agents for the same purposes forwhich prostacyclin is employed.

These essential material constituting a disclosure of the preparationand use of the novel compounds of the present invention is incorporatedhere by reference from U.S. Pat. No. 4,123,441.

SUMMARY OF THE INVENTION

The present invention particularly provides: a compound of the formula##STR1## wherein W₁ is α-OH:β-H, α-H:β-OH, oxo, methylene, α-H:β-H,α-CH₂ OH:β-H;

wherein L is

(1)--(CH₂)_(d) --C(R₂)₂ --, or

(2)--O--CH₂ --Y--,

wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro, being thesame or different with the proviso that one R₂ is not methyl when theother is fluoro, and Y is a valence bond, --CH₂ --or --(CH₂)₂ --,

wherein Q is oxo, α-H:β-H, α-OH:β-R₈ or α-R₈ :β-OH

wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive,

wherein R₉ is hydrogen, methyl, or ethyl, and wherein R₁₈ is hydrogen,alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12 carbonatoms, inclusive, phenyl, or phenyl substituted with alkyl of one to 4carbon atoms, inclusive;

wherein R₄ is

(1) --CR₅ R₆ --C_(g) H_(2g) --CH₃

(2) --CR₅ R₆ --Z--(Ph)

(3) cis--CH₂ --CH═CH--CH₂ CH₃

wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive,with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ --and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4carbon atoms, inclusive, or fluoro, being the same or different, withthe proviso that one of R₅ and R₆ is fluoro only when the other ishydrogen or fluoro and the further proviso that neither R₅ nor R₆ isfluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--)or C_(j) H_(2j) wherein C_(J) H_(2j) is a valence bond or alkylene ofone to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusivebetween CR₅ R₆ -- and the (Ph); wherein (Ph) is phenyl or phenylsubstituted by (T)s, wherein T is alkyl of one to 4 carbon atoms,inclusive, fluoro, chloro, trifluoromethyl, or --OR₇ --, wherein R₇ isalkyl of one to 4 carbon atoms, inclusive, and s is zero, one, 2, or 3,with the proviso that not more than two T's are other than alkyl andwhen s is 2 or 3 the T's are either the same or different;

wherein R₁₉ is chloro, bromo, or iodo; and wherein X is

(1) trans--CH═CH--

(2) cis--CH═CH--

(3) --C.tbd.C-- or

(4) --CH₂ CH₂ --.

With regard to the divalent substituents described in the claims, e.g.,Q and W₁, these divalent radicals are defined as α--R_(i) :β--R_(j),where R_(i) represents a substituent of the divalent moiety of the alphaconfiguration with respect to the cyclopentane and R_(j) represents asubstituent of the divalent moiety of the beta configuration withrespect to the cyclopentane ring. Accordingly, when Q is defined asα--OH:β--R₈, the hydroxy of the Q moiety is in the alpha configuration,i.e., as in prostacyclin, and the R₈ substituent is in the betaconfiguration. Not all carbon atoms to which such divalent moieties areattached represent asymmetric centers. For example, when both valencebonds are to hydrogen (e.g., W₁ or Q is α--H:β--H), then no asymmetriccenter is present.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention particularly relates to the following chemicalcompounds:

2-Decarboxy-2-aminomethyl-4ξ-iodo-9-deoxy-5ξ,9α-epoxy-PGF₁ ;

2-Decarboxy-2-aminomethyl-4ξ-bromo-9-deoxy-5ξ,9α-epoxy-PGF.sub.1 ;

2-Decarboxy-2-aminomethyl-4ξ-iodo-9-deoxy-5ξ,9αepoxy-15-keto-PGF₁ ;

2-Decarboxy-2-aminomethyl-4ξ-iodo-9-deoxy-5ξ,9α-epoxy-15-deoxy-PGF₁ ;and

2-Decarboxy-2-aminomethyl-4ξ-iodo-9-deoxy-5ξ,9α-epoxy-17-phenyl-18,19,20-trinor-PGF₁.

I claim:
 1. A compound of the formula ##STR2## wherein W₁ is α-OH:β-H,α-H:β-OH, oxo, methylene, α-H:β-H, α-Ch₂ OH:β-H;wherein L is --(CH₂)_(d)--C(R₂)₂ --,wherein d is zero to 5, R₂ is hydrogen, methyl, or fluoro,being the same or different with the proviso that one R₂ is not methylwhen the other is fluoro, wherein Q is oxo, α--H:β-H, α--OH:β-R₈ orα--R₈ :β--OH wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms,inclusive, wherein R₉ is hydrogen, methyl, or ethyl, and wherein R₁₈ ishydrogen, alkyl of one to 4 carbon atoms, inclusive, aralkyl of 7 to 12carbon atoms, inclusive, phenyl, or phenyl substituted with alkyl of oneto 4 carbon atoms, inclusive; wherein R₄ is(1) --CR₅ R₆ --C_(g) H_(2g)-CH₃ (2) --CR₅ R₆ --Z--(Ph) (3) cis--CH₂ --CH═CH--CH₂ CH₃ wherein C_(g)H_(2g) is alkylene of one to 9 carbon atoms, inclusive, with one to 5carbon atoms, inclusive, in the chain between --CR₅ R₆ -- and terminalmethyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms,inclusive, or fluoro, being the same or different, with the proviso thatone of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro andthe further proviso that neither R₅ nor R₆ is fluoro when Z is oxa(--O--); wherein Z represents an oxa atom (--O--) or C_(j) H_(2j)wherein C_(j) H_(2j) is a valence bond or alkylene of one to 9 carbonatoms, inclusive, with one to 6 carbon atoms, inclusive between CR₅ R₆--and the (Ph); wherein (Ph) is phenyl or phenyl substituted by (T)s,wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro,trifluoromethyl, or --OR₇ --, wherein R₇ is alkyl of one to 4 carbonatoms, inclusive, and s is zero, one, 2, or 3, with the proviso that notmore than two T's are other than alkyl and when s is 2 or 3 the T's areeither the same or different; wherein R₁₉ is chloro, bromo, or iodo; andwherein X is (1) trans--CH═CH-- (2) cis--CH═CH-- (3) --C.tbd.C-- or (4)--CH₂ CH₂ --.
 2. A compound according to claim 1, wherein W is α-OH:β-H.3. A compound according to claim 2, wherein L is --(CH₂)_(n) --, n being2, 3, or 4, wherein Q is oxo or α--OH:β--R₈ and wherein R₈ is hydrogen,methyl, or ethyl, and wherein R₄ is n-pentyl, 1,1-dimethylpentyl,1,1-difluoropentyl, phenoxymethyl or phenylethyl.
 4. A compoundaccording to claim 3, wherein X is trans--CH═CH--.